rs193922264
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000162.5(GCK):c.1130G>T(p.Arg377Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R377C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
GCK
NM_000162.5 missense
NM_000162.5 missense
Scores
11
2
1
Clinical Significance
Conservation
PhyloP100: 6.10
Genes affected
GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
?
In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000162.5
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr7-44145621-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 585908.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
?
Variant 7-44145620-C-A is Pathogenic according to our data. Variant chr7-44145620-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 872751.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.1130G>T | p.Arg377Leu | missense_variant | 9/10 | ENST00000403799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.1130G>T | p.Arg377Leu | missense_variant | 9/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Nov 24, 2023 | The c.1130G>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to leucine at codon 377 (p.(Arg377Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate: PMIDs: 21348868, 30245511, internal lab contributors). At least two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L or negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1129C>T p.(Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Arg377Leu). Another missense variant, c.1129C>A p.Arg377Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023) : PS4_Moderate, PP2, PP3, PM2_Supporting, PP4_Moderate, PM5_Supporting. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2023 | Variant summary: GCK c.1130G>T (p.Arg377Leu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234572 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1130G>T has been reported in the literature in individuals affected with features of Monogenic Diabetes (example, Osbak_2009, Borowiec_2012, Ma_2019, Zhou_2020, unpublished observations from the Clingen MODY expert panel). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21348868, 30245511, 19790256, 32375122). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
Sift4G
Pathogenic
D;D;D;D;D;D
Polyphen
D;.;D;D;D;D
Vest4
MutPred
0.98
.;.;Loss of disorder (P = 0.0292);.;.;.;
MVP
MPC
2.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at